Joanne Engel, M.D., Ph.D. is an assistant professor in the Department of Medicine at UCSF. Her long-term interests center upon bacterial pathogenesis as it relates to Infectious Diseases; her short term goals are to study the pathogenesis of chlamydial infections. Her graduate and postdoctoral training in Molecular and Cell Biology combined with her clinical training in Internal Medicine and infectious Diseases affords her a thorough background and a unique perspective to pursue these studies. She has a fully equipped lab in the Division of Infectious Diseases and the full support of the Department of medicine for her research. She has co- appointments in the two major graduate programs, giving her the opportunity to train exceptional graduate students. She has extensive interactions and collaborations with faculty and labs in the Biochemistry, Genetics, and Cell Biology Divisions. The next 5 years are critical to her maturation as a basic scientist and her ability to maintain a first-class research effort. An RCDA award would facilitate this by significantly decreasing her clinical load and teaching obligations, so that she may devote 85% of her time to research. The remaining 15% time will be devoted to research- related activities including clinical duties (that would allow her to maintain the clinical skills and expertise necessary for her research) and teaching. Chlamydia trachomatis is the leading cause of sexually transmitted diseases in the country and a major cause of blindness in third world countries. There are several unique aspect of the life cycle of this obligate intracellular parasite of humans that are key to its pathogenesis. These include (i) its unusual intracellular developmental life cycle and (ii) its ability to enter a non-phagocytic epithelial cell and survive within the hostile intracellular environment of the eukaryotic cytoplasm sequestered within a membrane bound compartment which evades fusion with lysosomes. The intimate interactions between chlamydia and its eukaryotic host are likely to involve natural biological pathways of the eukaryotic cell that the parasite usurps for its own survival. Remarkably little is known about chlamydial gene regulation or chlamydia-eukaryotic cell interactions, in part due to the difficulty in growing large quantities of the organism in tissue culture, the lack of chlamydial mutants, and the failure to develop a viable gene transfer system despite intense efforts, culminating in the inability to genetically manipulate these organisms. Study of these processes will yield insights into chlamydial disease pathogenesis as well as insights into eukaryotic cell biology. The proposal seeks to (i) develop an in vitro system to dissect the control of transcription initiation in Chlamydia (ii) explore the mechanisms by which chlamydia avoids lysosomal destruction and (iii) understand the interaction between chlamydia and the host cell signal transduction pathways. From these studies may emerge new therapeutic approaches to treating or preventing chlamydial infections.